The nargenicins are a class of polyketide macrolide antibiotics with a tricyclic lactone containing a unique ether bridge. See Kallmerten, 1995, Studies in Natural Products Chemistry 17:283-310. The first nargenicin, nargenicin A1, was originally isolated from Nocardia argentinensis. See Celmer et al., 1980, J. Am. Chem. Soc. 102:4203-4209. Nargenicin has been demonstrated to be effective towards gram-positive bacteria and, in particular, has been shown to have strong antibacterial activity against methicillin-resistant Staphylococcus aureus. See Sohng et al., 2008, Arch Pharm Res 31: 1339-1345 and Korean Patent Application No. KR2009093733A. It has also been contemplated for use as a treatment for neoplastic diseases and neurodegenerative diseases. See, e.g., Kim et al., 2009, Biochem Pharmacol 77:1694-1701, and Korean Patent Application No. KR2010071835A.
Other nargenicins, included, nargenicin B1, nargenicin B2, nargenicin B3, and nargenicin C1, are described in Magerlein et al., 1982, J. Antibiotics 35:254 and U.S. Pat. Nos. 4,436,747; 4,448,970; and 4,605,624.
Mycobacterium is a genus of bacterium, neither truly gram-positive nor truly gram-negative, including pathogens responsible for tuberculosis (M. tuberculosis) and leprosy (M. leprae). Tuberculosis (TB), in particular, despite the availability of anti-TB drugs such as isoniazide and rifampin, is considered to be one of the world's deadliest diseases. According to World Health Organization, in 2012, there were 8.6 million new TB cases and 1.3 million TB deaths. See, Global tuberculosis report 2013 published by the World Health Organization. Complicating the TB epidemic is the rising tide of multi-drug-resistant strains, and the deadly association with HIV. People who are HIV-positive and infected with TB are 30 times more likely to develop active TB than people who are HIV-negative and TB is responsible for the death of one out of every three people with HIV/AIDS worldwide. See, e.g., Kaufmann et al., 1993, Trends Microbiol. 1:2-5 and Bloom et al., 1998, N. Engl. J Med. 338:677-678.
Mycobacteria other than M. tuberculosis are increasingly found in opportunistic infections that plague the AIDS patient. Organisms from the M. avium-intracellulare complex (MAC), especially serotypes four and eight, account for 68% of the mycobacterial isolates from AIDS patients. Enormous numbers of MAC are found (up to 1010 acid-fast bacilli per gram of tissue), and consequently, the prognosis for the infected AIDS patient is poor.